tbuckley/cabot-search huggingface dataset:
Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types
Authors: Matthew C. Pahl, Carole Le Coz, Chun Su, Prabhat Sharma, Rajan M. Thomas, James A. Pippin, Emylette Cruz Cabrera, Matthew E. Johnson, Michelle E. Leonard, Sumei Lu, Alessandra Chesi, Kathleen E. Sullivan, Neil Romberg, Struan F. A. Grant, Andrew D. Wells
Journal: Genome biology (2022)

Abstract Background SARS-CoV-2 infection results in a broad spectrum of COVID-19 disease, from mild or no symptoms to hospitalization and death. COVID-19 disease severity has been associated with some pre-existing conditions and the magnitude of the adaptive immune response to SARS-CoV-2, and a recent genome-wide association study (GWAS) of the risk of critical illness revealed a significant genetic component. To gain insight into how human genetic variation attenuates or exacerbates disease following SARS-CoV-2 infection, we implicated putatively functional COVID risk variants in the cis-regulatory landscapes of human immune cell types with established roles in disease severity and used high-resolution chromatin conformation capture to map these disease-associated elements to their effector genes. Results This functional genomic approach implicates 16 genes involved in viral replication, the interferon response, and inflammation. Several of these genes (PAXBP1, IFNAR2, OAS1, OAS3, TNFAIP8L1, GART) were differentially expressed in immune cells from patients with severe versus moderate COVID-19 disease, and we demonstrate a previously unappreciated role for GART in T cell-dependent antibody-producing B cell differentiation in a human tonsillar organoid model. Conclusions This study offers immunogenetic insight into the basis of COVID-19 disease severity and implicates new targets for therapeutics that limit SARS-CoV-2 infection and its resultant life-threatening inflammation.
Interim analysis of a phase I study of SNK01 (Autologous Nongenetically Modified Natural Killer Cells with Enhanced Cytotoxicity) and avelumab in advanced refractory sarcoma.
Authors: Sant P. Chawla, Victoria S. Chua-Alcala, Erlinda Maria Gordon, Ted T. Kim, William Feske, Brenda L. Gibson, Paul Y Chang, Debra Robinson, Paul Y. Song
Journal: Journal of Clinical Oncology (2022)

11517 Background: For patients (pts) with advanced sarcomas in the relapsed/refractory setting, there are very few if any effective salvage treatment options. The likelihood of response and/or tumor control only diminishes with each subsequent line of therapy. Monotherapy of PD-L1 inhibitors has shown modest to no activity in most sarcomas, especially in tumors that have little to no PD-L1 expression. Natural killer (NK) cells have recently been implicated in the antitumor response to immune checkpoint inhibitors with some evidence suggesting a role in PD-L1 negative tumors. SNK01 is a first-in-kind, autologous nongenetically modified NK cell therapy with highly enhanced cytotoxicity and over 90% activating receptor expression which can be consistently produced from heavily pretreated pts. Avelumab is an anti-PD-L1 immunotherapy with dual engagement of both the adaptive and innate immune systems. We hypothesized that this combination would be safe, and together better overcome the immunosuppressive tumor microenvironment. Methods: In this Phase I study (NCT03941262), cohort 4 is comprised of up to 18 pts treated with 800 mg of avelumab + 4 x 10 9 SNK01 cells every two weeks via IV Infusion. Pts were eligible regardless of PD-L1 status and permitted to continue treatment indefinitely until progression or unacceptable toxicity. The primary endpoint is safety. The secondary endpoints include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Results: As of February 1, 2022, 15 pts with advanced refractory sarcoma have been enrolled. Median age is 50 (range 20-75) and 8 were male. Pts had a median of 5 lines of prior therapy (range 1-8). The subtypes included 6 leiomyosarcoma, 2 osteosarcoma, 1 pleomorphic liposarcoma, 1 Ewing’s sarcoma, 1 epithelioid sarcoma, 1 epithelioid mesothelioma, 1 endometrial stromal sarcoma, and 1 sarcoma NOS. There were three Grade 2 or 3 adverse events related to avelumab, but unrelated to SNK01. Best objective response by RECIST 1.1 was PR in 2 pts (ORR of 13.3%) and SD in 3 pts. Median PFS is 11.14 weeks. Several pts had PD-L1 negative disease and response appears to be independent of PD-L1 status. Of pts who progressed in this cohort, several reported an overall improvement in their QoL and some pts became eligible to be treated with additional salvage chemotherapy, resulting in some additional clinical response. Conclusions: SNK01 combined with avelumab was safe and well tolerated and appears to have some clinical activity against several types of heavily pretreated advanced sarcoma, independent of PD-L1 status. It may also keep rapidly progressing disease stable enough to allow additional cytotoxic chemotherapy. A proposed study expansion is planned. Clinical trial information: NCT03941262.
Association between the Affordable Care Act Medicaid expansion and survival in young adults newly diagnosed with cancer.
Authors: Xu Ji, Kewei Shi, Sharon M. Castellino, Ann C. Mertens, Jingxuan Zhao, K. Robin Yabroff, Xuesong Han
Journal: Journal of Clinical Oncology (2022)

1502 Background: Medicaid expansion through the Affordable Care Act (ACA), implemented by 26 states in January 2014 and 13 more states in later years, has been shown to improve insurance coverage and early diagnosis of cancer in young adults (YAs). Little is known about whether these improvements translate to a survival benefit in this population. We evaluated the association between the ACA Medicaid expansion and 2-year overall survival among YAs newly diagnosed with cancer. Methods: Using the National Cancer Database, we identified 345,414 YAs aged 18-39 years diagnosed with cancer between 2010 and 2017. YAs diagnosed pre-expansion were followed through September 30, 2013 or three months before Medicaid expansion implementation for late-expansion states, and YAs diagnosed post-expansion were followed through December 31, 2019. We applied the difference-in-difference (DD) method to estimate changes in 2-year overall survival before and after Medicaid expansion, in expansion- versus non-expansion states, controlling for key sociodemographic factors. DD analyses were performed for YAs overall, and stratified by cancer type, stage at diagnosis, race/ethnicity, comorbidity, and facility type. Results: Among all YAs, 2-year overall survival increased more in expansion states (90.39% pre-expansion to 91.87% post-expansion) than in non-expansion states (88.98% pre-expansion to 90.05% post-expansion), resulting in a net increase of 0.53 percentage points (ppt; 95% confidence interval [CI] = 0.11 to 0.95 ppt). The increase in 2-year overall survival in expansion states versus non-expansion states was greatest among subgroups of patients with female breast cancer (DD = 1.20 ppt; 95% CI = 0.28 to 2.13 ppt) and patients with stage IV disease at diagnosis (DD = 2.51 ppt; 95% CI = 0.28 to 4.74 ppt). Additionally, greater improvement in 2-year overall survival associated with the expansion was seen among racial/ethnic minority YAs (including Hispanic, non-Hispanic Black, and non-Hispanic others; DD = 0.98 ppt; 95% CI = 0.10 to 1.86 ppt) than their non-Hispanic White peers (DD = 0.41 ppt; 95% CI = -0.06 to 0.89 ppt), among patients treated in community cancer programs (DD = 1.10 ppt; 95% CI = 0.32 to 1.88 ppt) than academic comprehensive cancer programs (DD = 0.12 ppt; 95% CI = -0.52 to 0.77 ppt), and among patients with two or more comorbidities (DD = 6.37 ppt; 95% CI = 0.68 to 12.06 ppt) than patients with no comorbidity (DD = 0.48 ppt; 95% CI = 0.04 to 0.91 ppt). Conclusions: We provide the first evidence on the association between ACA Medicaid expansion and improved overall survival among YAs newly diagnosed with cancer. Survival benefits are notable among racial/ethnic minority patients and patients with high healthcare needs, and by patients’ treatment facility type.
Cancer risk factors and cancer in transgender versus cisgender people: Real-world data from a tertiary health care institution.
Authors: Ash B. Alpert, Sabrina Jamileh Sayegh, Myla S. Strawderman, Scott Cunliffe, Ana Paula Cupertino, Catherine Cerulli, Jennifer J. Griggs
Journal: Journal of Clinical Oncology (2022)

6538 Background: Data are sparse regarding the prevalence of cancer and cancer risk factors among transgender people. Transgender people experience structural stigma and extreme rates of violence that may contribute to cancer through multiple mechanisms. The purpose of this study was to assess cancer risk factors and cancer in transgender people in a single institutional electronic health record (EHR) and compare the rates to those among cisgender, or non-transgender, people. Methods: Using a combination of structured gender identity data, diagnosis codes, and keyword searches, we identified a cohort of transgender people seen at our institution, a large tertiary care center. We next identified a cohort of cisgender people matched by age, year of first encounter in our EHR, and years of follow-up. Among these cohorts, we searched for cancer, premalignant lesions, human immunodeficiency virus (HIV), human papilloma virus (HPV), and hepatitis and assessed body mass index (BMI) and smoking status through structured EHR fields. Lastly, we compared the prevalence of cancer, premalignant lesions, and cancer risk factors between the two cohorts using chi-square tests. If expected cell sizes were &lt;5, exact tests were used. Results: We identified cohorts of 923 transgender and 1846 cisgender people matched by age, follow-up time, and year of the first encounter. Rates of smoking (42 versus 34%, p &lt; 0.0001), BMI ≥ 40 (21% versus 13%, p &lt; 0.0001), and HIV (3 versus 0%, p &lt; 0.0001) were significantly higher among transgender compared with cisgender people. Rates of premalignant lesions and cancer did not significantly differ between cohorts. Conclusions: In this large sample of patients seen at our institution, rates of several cancer risk factors were higher for transgender than cisgender people. No differences were demonstrated in prevalence of premalignant lesions and cancer between groups. These data require confirmation in larger national datasets. Interventions that decrease structural oppression and provide support for tobacco cessation, decreased transmission of HIV, and access to high-quality food and exercise are also called for. [Table: see text]
Partial ablation and total ablation with High Intensity Focused Ultrasound (HIFU) compared to Radical Prostatectomy (RP): A propensity score-matched study
Authors: C. Ye, G. Jung, H. Kim, J.K. Kim, J.J. Oh, S. Lee, S.J. Jeong, S.K. Hong, S-S. Byun, H. Lee
Journal: European Urology (2022)
ATRT-25. CERVICAL ATYPICAL TERATOID RHABDOID TUMOR IN PEDIATRIC PATIENTS: A STUDY OF THE LAST DECADE
Authors: Amanda Cyntia Lima Fonseca Rodrigues, Letícia dos Santos Louro, Maria Eduarda Geddo Kostakis, Milena Henriques Fialho, Kananda Oliveira Garcia Ruiz, Beatriz Patriota Saraiva Costa, Monique Benemérita Vilela Gomes
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Atypical rhabdoid teratoid tumor (AT/RT) is an extremely rare primary tumor of the central nervous system (CNS) with a high incidence in children under 3 years of age. The existing literature involving this tumor is scarce, even though AT/RT is considered one of the most malignant brain tumors due to its aggressive course and short survival time, which generally does not exceed 1 year. METHODS: The “PubMed” database was used for this study using the MeSH Terms “Child” and “Atypical Teratoid Rhabdoid Tumor” and the filter “Case Reports” in order to carry out a study with the clinical cases of the last decade and the involvement of this tumor in the cervical region of pediatric patients. 96 articles were found, however, only 10 articles were selected for this review. RESULTS: It is possible to affirm that the cases of AT/RT are found in greater numbers in children under 3 years of age and are predominantly located in the cervical region when they affect the spinal cord. In addition, MRI usually shows a solid heterogeneous mass that results in the appearance of symptoms, since the mass compresses the conus medullaris and consequently generates pain in the spine. The prognosis is reported to be a difficult one and the median patient survival time is less than one year. CONCLUSION: Therefore, AT/RT is rare, fatal, primary and malignant in the CNS that have a high degree of recurrence and dissemination. The diagnosis is made through anatomopathological examination and the loss of INI-1 expression constitutes an important finding for its conclusion. Treatment is multimodal and may combine surgery, chemotherapy and radiotherapy.
EPEN-02. Adaptive Convergence of Methylomes Reveals Epigenetic Drivers and Boosters of Repeated Relapses in Patient-matched Childhood Ependymomas and Identifies Targets for Anti-Recurrence Therapies
Authors: Sibo Zhao, Jia Li, Huiyuan Zhang, Lin Qi, Yuchen Du, Mari Kogiso, Frank K Braun, Yulun Huang, Wan-Yee Teo, Patricia Baxter, Adekunle Adesina, Yongcheng Song, Deqiang Sun, Xiao-Nan Li
Journal: Neuro-Oncology (2022)

Abstract Ependymoma (EPN) is the third most common brain tumor in children and frequently recurs. Here, we report an integrated longitudinal analysis of epigenetic, genetic and tumorigenic changes in 30 patient-matched repeated relapses obtained from 10 pediatric patients to understand the mechanism of recurrences. Genome-wide DNA methylation analysis revealed stable molecular subtypes and convergent epigenetic reprogramming during serial relapses of the 5 RELA and 5 PFA EPNs that paralleled with elevated patient-derived orthotopic xenograft (PDOX) (13/27) formation in the late relapses. Differentially methylated CpGs (DMCs) preexisted in the primary tumors and persisted in the relapses (driver DMCs) were detected, ranging from 51 hypo-methylated in RELA to 148 hyper-methylated DMCs in PFA tumors; while newly acquired DMCs sustained in all the relapses but was absent in the primary tumors (booster DMCs) ranged from 38- 323 hyper-methylated DMCs in RELA and PFA EPNs, respectively. Integrated analysis of these DMC associated DNA methylation regions (DMRs) and RNAseq in both patient and PDOX tumors identified a small fraction of the differentially expressed genes (4.6±4.4% in RELA and 4.5±1.1% in PFA) as regulated by driver DMRs (e.g., up-regulated CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and booster DMRs (including the sole upregulated PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). Most these genes were novel to EPN relapses. Seven DMCs in RELA and 22 in PFA tumors were also identified as potential relapse predictors. Finally, integrating DNA methylation with histone modification identified LSD1 as a relapse driver gene. Combined treatment of a novel inhibitor SYC-836 with radiation significantly prolonged survival times in two PDOX models of recurrent PFA. This high-resolution epigenetic and genetic roadmap of EPN relapse and our 13 new PDOX models should significantly facilitate biological and preclinical studies of pediatric EPN recurrences.
Brain metastases in the setting of stable extracranial disease: A systematic review and meta-analysis.
Authors: Alyssa Y. Li, Karolina Gaebe, Amna Zulfiqar, Grace Lee, Katarzyna Joanna Jerzak, Arjun Sahgal, Anders W. Erickson, Sunit Das
Journal: Journal of Clinical Oncology (2022)

2022 Background: Intracranial metastatic disease (IMD) is a life-altering complication for many patients with cancer. Improvements in systemic therapies have transformed the epidemiology of IMD, with some patients presenting with IMD in the context of stable extracranial disease (IMD-SECD). Among patients with metastases in other sites with similarly stable systemic disease, surgical resection and targeted therapy can result in long-term disease control and extended overall survival (OS), yet little is known about the clinical outcomes for patients with IMD-SECD. Methods: We searched MEDLINE, EMBASE, CENTRAL, and grey literature sources up to June 21, 2021 for studies reporting brain metastasis (BrM) with controlled extracranial disease (ECD) as well as IMD-SECD secondary to any primary cancer (criteria: presence of BrM and ≤2 extracranial metastatic sites, with no prior second-line chemotherapy and second-line brain-directed therapy). In studies comparing IMD-SECD and IMD patients, hazard ratios (HR) for OS and intracranial progression-free survival (iPFS) were pooled using random-effects meta-analysis, while medians for OS were estimated from single-arm IMD-SECD studies based on distribution-free summary survival curves. Results: Of 1067 records identified, 68 studies involving 5325 patients with IMD-SECD were included. Patients with IMD-SECD had prolonged OS (HR 1.93; 95% CI, 1.44-2.59; n = 10 studies; n = 877 patients) and iPFS (HR 1.59; 95% CI 1.31-1.92; n = 4 studies; n = 673 patients) compared with IMD patients. Subgroup analysis of patients with BrM and controlled versus uncontrolled ECD found prolonged OS with controlled ECD (HR 2.46; 95% CI, 1.36-4.44; n = 4 studies; n = 135 patients). Pooled median OS for all IMD-SECD patients was 20.85 months (mo) (95% CI, 16.35-25.98; n = 27 studies; n = 2159 patients). Stratification by primary cancer type showed median OS 20.18 mo (95% CI, 10.43-38.20; n = 2 studies; n = 109 patients) and 27.46 mo (95% CI, 18.27-49.66; n = 13 studies; n = 497 patients) for patients with IMD-SECD secondary to breast cancer and non-small cell lung cancer, respectively. Conclusions: Patients with IMD-SECD demonstrate prolonged OS and iPFS compared with patients with IMD, who may have more extensive systemic disease. Our results suggest that patients with IMD-SECD may represent a distinct subpopulation of patients with IMD with a uniquely favourable prognosis. It is possible that aggressive and timely treatment may significantly prolong survival for these patients. Future prospective trials should aim to investigate the efficacy of current treatment regimens in patients with IMD-SECD to further clarify optimal treatment pathways in this unique population of patients.
The National Deficit of Black and Hispanic Physicians in the US and Projected Estimates of Time to Correction
Authors: Hector Mora, Adetokunbo Obayemi, Kevin Holcomb, Maurice Hinson
Journal: JAMA Network Open (2022)

This cross-sectional study of US population and physician workforce data projects rates at which medical school matriculation would have to increase for Black and Hispanic medical students to reach equal representation in the workforce.
Overall survival benefits of first-line treatments for Asian patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer harboring L858R mutation: A systematic review and network meta-analysis.
Authors: Sik-Kwan Chan, Cheuk-Wai Choi, Victor Ho-Fun Lee
Journal: Journal of Clinical Oncology (2022)

e21064 Background: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and their biologically synergistic combinations with other treatments for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) as first-line treatment for EGFR-mutant NSCLC have recently gained considerable attention, in particular for those with L858R mutation, a known worse subgroup compared to exon 19 deletions. However, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with the L858R mutation remains unclear. Methods: We performed a systematic review and fixed-effects frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE Ovid, Embase, Cochrane Library, CINAHL Databases, trial registries and other sources. P-score was used to rank the treatments. We included published and gray sources of randomized clinical trials comparing two or more treatments in the first line setting for Asian patients with advanced EGFR mutated NSCLC harboring L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD42022295897). Results: Eighteen trials involved 1852 Asian patients and 12 treatments: including EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucizumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with the L858R mutation had no significant OS benefits from all EGFR TKIs or combination treatments over chemotherapies. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib and erlotinib plus bevacizumab were shown to be consistent in yielding the best progression-free survival benefit, with their corresponding P-scores of 93%, 79%, 77% and 70%. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, which caused the most adverse events of grade 3 or higher. Conclusions: In Asian patients with advanced NSCLC harboring L858R mutation, EGFR TKIs and combination treatments demonstrated no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with the L858R mutation.
LGG-33. A 40-year cohort study of evolving hypothalamic dysfunction in 90 infants and young children (&amp;lt;3y) with optic pathway gliomas
Authors: Stefania Picariello, Manuela Cerbone, Felice D'Arco, Hoong-Wei Gan, Patricia O’Hare, Kristian Aquilina, Enrico Opocher, Darren Hargrave, Helen Alexandra Spoudeas
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. METHODS: We aimed to assess presenting disease, tumour location and treatment factors implicated in the evolution of neuroendocrine, metabolic and neuro-behavioural morbidity in children diagnosed before their 3rd birthday and followed over four decades (1981- 2020). RESULTS: Ninety infants/young children followed-up for 9.5 years (range 0.5-25.0) were included in the study. Fifty-two (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) had hypothalamic involvement (H+) and lower endocrine event free survival (EEFS) rates. Median time to first endocrine event was 3.4 years, with EEFS declining up to 13.6 years after diagnosis. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs 46%, p=0.001), H+ (OR 6.1 95% CI 1.7 – 21.7, p 0.005), radiotherapy (OR 16.2, 95% CI 1.7 – 158.6, p=0.017) and surgery (OR 4.8 95% CI 1.3- 17.2, p=0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and clustered with the endocrinopathies. Posterior pituitary disorders were recorded in 15 subjects (16.7%), only after surgery and/or as a consequence of hydrocephalus in those with suprasellar tumours and hypothalamic disease. Neuro-behavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1 – 5.9, p=0.043) and radiotherapy (OR 23.1 C.I. 2.9 – 182, p=0.003). CONCLUSIONS: Very young children with OPHG carry a high risk of endo-metabolic and neuro-behavioural comorbidities which deserve better understanding and timely/parallel support from diagnosis to improve outcomes. These evolve in a complex hierarchical pattern overtime whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies.